Pyridazine derivatives, manufacturing method and related composition

ABSTRACT

Ultraviolet absorbents and photostabilizers have an excellent absorption ability in a wide range of ultraviolet rays, and also have high stability and high safety. The ultraviolet absorbent and photostabilizer include a pyridazine derivative of the formula (1):  
                 
 
     or salts thereof. Also, described are methods for manufacturing said pyridazine derivative and/or this salts thereof comprising the process of reacting at least 10 wt % of 4,5-dichloro-3-hydroxypyridazine or 4,5-dibromo-3-hydroxypyridazine or mixtures thereof with at least 20 vol % of morpholine in reaction solution at 70° C. or higher. The ultraviolet absorbents photostabilizers include said pyridazine derivative and/or salts thereof as effective ingredient. An ultraviolet ray absorption composition and an external preparation for skin are also included.

RELATED APPLICATIONS

[0001] This application claims priority from Japanese Patent applicationNo. 11-356201, filed Dec. 15, 1999, which is incorporated herein byreference.

FIELD OF THE INVENTION

[0002] The present invention relates to pyridazine derivatives, a methodfor its manufacture, compositions thereof including ultravioletabsorbents and photostabilizers, ultraviolet-ray-absorptive compositionsand external preparations for skin.

BACKGROUND OF THE INVENTION

[0003] Ultraviolet rays of wavelength 290 nm or less in sunlight areabsorbed by the ozone layer. Accordingly, these do not reach the surfaceof the earth. However, as the ultraviolet rays of 290 to 400 nm reachthe surface of the earth, these ultraviolet rays have various effects.In skin chemistry, the ultraviolet rays of the wavelength of 290 nm to320 nm cause the formation of erythema and blistering. It is known thatthese ultraviolet rays cause acceleration of melanism and chromatosis.The long wavelength ultraviolet rays of 320 to 400 nm causes themelanism of skin immediately after irradiation. Also, since the energyreaches to an corium of skin, these ultraviolet rays influence theelastica in the walls of blood vessels and connective tissue. Theseultraviolet rays of middle wavelength to long wavelength accelerate theaging of a skin. Also, it is thought that these ultraviolet rays are acause of the formation of stains, freckles, wrinkles and the like.

[0004] To protect the skin from such ultraviolet rays, ultravioletabsorbents have been used. These ultraviolet absorbents include, forexample, benzotriazole derivatives, benzophenone derivatives, salicylicacid derivatives, p-aminobenzoic acid derivatives, cinnamic acidderivatives, and urocanic acid derivatives.

[0005] These ultraviolet absorbents are used in photostabilizers ofcolorant, perfume, drug, etc., in medical supplies and cosmetics.

[0006] Also, ultraviolet absorbents are used in fields other thanmedical supplies and cosmetics. For example, they are added to thevarious materials of coating, dye, pigment, resin, synthetic rubber,latex, film and fiber. As these are given absorbing ability forultraviolet rays, a product, or paints or films coating a product can beprotected from the ultraviolet rays. The ultraviolet absorbent is usedto maintain quality by preventing degradation, degeneration and so on bythe ultraviolet rays.

[0007] It is desirable that an ultraviolet absorbent is able to absorbthe ultraviolet rays of all the wavelength range of 290 nm to 400 nmwhich reach the surface of the earth. Also, when an ultravioletabsorbent is included in an external preparation for skin, it isimportant that the ultraviolet absorbent is not decomposed by sunlightexposure. Also, it is important that the ultraviolet absorbent does notcause skin irritation.

[0008] However, conventional ultraviolet absorbents do not alwayssatisfy these preferences. Conventional ultraviolet absorbents sometimescause coloring and deposition due to ultraviolet rays shielding agentsin inorganic powders commonly used in external preparations for skin.Also, a satisfactory photostabilizer compound has been needed.

[0009] Also, conventional ultraviolet rays absorbents in other fieldssublimate and volatilize by heating during sintering of paints and inthe forming of resin. In addition, these absorbents vaporize graduallyand become less effective with the passing of time, even if it is notheated.

SUMMARY OF THE INVENTION

[0010] The present invention is achieved in view of the foregoing priorart. The object of the present invention is to provide an ultravioletabsorbent, a photostabilizer and a manufacturing method, which have anexcellent absorbing ability in the wide ultraviolet rays wavelengthrange, that have high stability and safety. It is a another object ofthe present invention to provide an ultraviolet ray absorptioncomposition including said ultraviolet absorbent. It is further objectof the present invention to provide an external preparation for skinincluding said ultraviolet absorbent or said photostabilizer.

[0011] As a result of diligent study by the present inventors, it wasfound that a certain kind of pyridazine derivatives have theabove-mentioned properties and are excellent ultraviolet absorbents andphotostabilizers.

[0012] Namely, the present invention is pyridazine derivatives ofgeneral formula (1) and salts thereof. The compound of the presentinvention has excellent absorbing ability with respect to the wideultraviolet ray wavelength range. As it is very stable and safe, it isan excellent ultraviolet absorbent and photostabilizer.

[0013] A manufacturing method of the pyridazine derivatives comprisesthe process of reacting at least 10 wt % of4,5-Dichloro-3-hydroxypyridazine or 4,5-Dibromo-3-hydroxypyridazine orcombination thereof, with at least 20 vol % of morpholine in a reactionsolution at 70° C. or higher.

[0014] An ultraviolet absorbent of the present invention comprises saidpyridazine derivatives and/or salts thereof as an active ingredient.

[0015] An ultraviolet ray absorption composition of the presentinvention includes said ultraviolet absorbents.

[0016] A photostabilizer of the present invention comprises saidpyridazine derivatives and/or salts thereof, as an active ingredient. Itis preferable that said photostabilizer includes a sequestering agent.

[0017] An external preparation for skin of the present inventioncomprises said ultraviolet absorbents. Also, it is preferable that theexternal preparation for skin of the present invention includes aninorganic powder.

[0018] Also, an external preparation for skin of the present inventioncomprises said photostabilizer. It is preferable that said external skinpreparation includes a sequestering agent.

[0019] Also, in the external skin preparation of the present invention,it is preferable that said external preparation for skin includes 0.001wt % to 20 wt % of said pyridazine derivatives or salts thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020]FIG. 1 shows the ultraviolet absorption spectrum of pyridazinederivative (4,5-Dimorpholino-3-hydroxypyridazine) of the presentinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Pyridazine DerivativesAnd Salts Thereof

[0021] A pyridazine derivative of the present invention is shown in ageneral formula (1). This compound can be isomerized to general formula(1′), which is tautomer with the equilibrium like the following, undercertain conditions.

[0022] The pyridazine derivatives in the present invention are describedonly by the general formula (1) for convenience. However, the pyridazinederivatives in the present invention can be isomerized to a generalformula (1′) as a tautomer.

[0023] The chemical name of the pyridazine derivative of the presentinvention includes 4,5-Dimorpholino-3-hydroxypyridazine and4,5-Dimorpholino-3-hydroxypyridazine hydrochloride and the like.

[0024] A pyridazine derivative of the present invention can besynthesized by the followings method.

[0025] In the above-mentioned reaction formula, A represents a chlorineatom or bromine atom. The compound of a general formula (3) (when A is achlorine atom, 4,5-Dichloro-3-hydroxypyridazine; when A is a bromineatom, 4,5-Dibromo-3-hydroxypyridazine) can be synthesized by the methodof Chemische Berichte, 32, 543(1899) and so on in accordance with theabove-mentioned formula. The compounds of the general formula (2) can beeasily available. Namely, the compounds of a general formula (3) iseasily obtained by cyclic reaction of compounds of a general formula (2)and hydrazine. Also, the compounds of the general formula (3) (A ischlorine atom) which can be available from ALDRICH Inc. Also, pyridazinederivatives of the present invention were obtained by reacting 10 wt %or more of a compound of the general formula (3) and 20 vol % or more ofmorpholine in a reaction solution at 70° C. or higher. In the case wherethe concentration of compounds of the general formula (3) in thereaction solution is less than 10 wt %, in the case where theconcentration of morpholine in the reaction solution is less than 20 vol%, and in the case where reaction temperature is lower than 70° C., itwas difficult to obtain pyridazine derivatives of the present invention.

[0026] Also, the pyridazine derivatives of the present invention includeinorganic acid salt or organic acid salt made by published methods.Examples of inorganic acids include hydrochloric acid, sulfuric acid,phosphoric acid, hydrobromic acid. Examples of organic acids includeacetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid,citric acid, methanesulfonic acid, p-toluenesulfonic acid.

Ultraviolet Absorbent And External Preparation For Skin

[0027] An ultraviolet absorbent having as its principal componentpyridazine derivative or salt thereof can be included in variousproducts. An external skin preparation including this absorbent issuitable. An external preparation for skin having the ultravioletabsorbent of the present invention demonstrates an excellent ultravioletray prevention effect. Also, since the ultraviolet absorbent does notdecompose under sunlight exposure, the effect is continued for a longtime. Also, it does not cause problems for the skin. Accordingly, it isespecially useful as the external skin preparation for sun screen.

[0028] Also, to increase the ultraviolet rays shielding effect in anexternal skin preparation for sun screen, it is preferred that anultraviolet absorbent of an organic compound and an ultraviolet rayshielding agent of an inorganic powder are included. Also, manycosmetics for makeup include inorganic powder. However, use of anorganic ultraviolet absorbent and inorganic powder may causediscoloration.

[0029] The ultraviolet absorbent of the present invention does not causediscoloration, when included with an inorganic powder in an externalskin preparation for skin. Therefore, it is possible to includeinorganic powder.

Inorganic Powder

[0030] In the present invention, an inorganic powder includes powder incosmetics and medical supplies. Examples of inorganic powder includetalc, kaolin, boron nitride, mica, sericite, muscovite, black mica,golden mica, synthetic mica, vermiculite, magnesium carbonate, calciumcarbonate, silicic anhydride, aluminum silicate, aluminum oxide, bariumsilicate, calcium silicate, magnesium cilicate, tungsten metal salt,magnesium, silica, zeolite, barium sulfate, calcined calcium sulfate,calcined gypsum, calcium phosphate, fluoroapatite, calcium phosphatehydroxide, ceramic powder, metal soap (zinc myristate, calciumpalmitate, aluminum stearate etc.). Also, examples of inorganic pigmentinclude titanium dioxide, zinc oxide, iron oxide, iron titanium oxide,carbon, low-valent titanium oxide, mango violet, cobalt violet, chromiumoxide, chromium hydroxide, cobalt titanium oxide, ultramarine, ironblue, titanium oxide coated mica, titanium oxide coated bismuthoxychloride, colored titanium oxide coated mica, bismuth oxychloride,fish scale flake.

Photostabilizer

[0031] The pyridazine derivatives and salts thereof of the presentinvention are useful as a photostabilizer. Especially, the compound isan excellent photostabilizer of colorants, perfumes and drugs in medicalsupplies and cosmetics. Also, the pyridazine derivatives and saltsthereof of the present invention can achieve a synergisticphotostabilization effect, by including a sequestering agent.

Sequestering Agent

[0032] In the present invention, pyridazine derivatives or salts thereofcan be used with a sequestering agent. Examples of sequestering agentsinclude sodium ethylenediaminetetraacetate (EDTA), trisodiumhydroxyethyl ethylenediamine triacetate(dihydrate), phosphoric acid,citric acid, ascorbic acid, succinic acid, gluconic acid, sodiumpolyphosphate, sodium metaphosphate, 1-hydroxyethane 1,1-diphosphate.

Use Of External Preparation For Skin

[0033] The external preparation for skin of the present invention mayincludes the above-mentioned ultraviolet absorbent or theabove-mentioned photostabilizer. Forms of the external preparation forskin of the present invention are not restricted if the effect of thepresent invention is demonstrated. Examples of forms of the externalpreparation for skin of the present invention include lotion, milkylotion, cream and essence for skin care cosmetics. Also, examples ofmakeup cosmetics include base cosmetics, foundation, lipstick, facecolor and eyeliner. Also, examples of cosmetics for hair and scalpinclude hair spray, hair tonic and hair liquid.

Amount Of Pyridazine Derivative Or Salts Thereof In An External SkinPreparation

[0034] When the external preparation for skin includes the pyridazinederivatives and/or salts thereof of the present invention, the amountdepends on the need for UV absorbing ability or photostabilizationability. Usually the preferable amount of pyridazine derivative and/orsalt thereof in a composition is 0.001 wt % to 20 wt %, more preferably0.01 wt % to 10 wt %. If the amount is less than 0.001 wt %, theultraviolet rays prevention effect or photostabilization effect mayinadequate. Also, if the amount is more than 20 wt %, it may bedifficult to maintain the form of external skin preparation.

Other Ingredients

[0035] The external preparation for skin of the present invention caninclude other ingredients often included in cosmetics and medicalsupplies. Examples of other ingredients include liquid fat and oil,solid fat and oil, wax, hydrocarbon, higher fatty acid, higher alcohol,ester, silicone, anionic surfactant, cationic surfactant, ampholyticsurfactants, nonionic surfactant, humectants, water-soluble highmolecular compounds, thickeners, film formers, lower alcohol, polyhydricalcohol, saccharides, amino acid, organic amine, pH adjustment agent,skin nutrition agents, vitamins, antioxidants, perfumes, powder,colorants and water and the like. These ingredients can be combined inexternal preparation for skin of the present invention if needed. Also,ultraviolet absorbents and photostabilizers other than the pyridazinederivatives of the present invention can be combined unless the objectsof the invention are thwarted.

Ultraviolet Absorptive Composition

[0036] The ultraviolet absorbent of the present invention can be used inproducts other than external skin preparation. For example, coating,dye, pigment, resin, synthetic rubber, latex, film, fiber and so on caninclude the ultraviolet absorbent of the present invention forultraviolet ray prevention. Since pyridazine derivatives of the presentinvention excel in heat stability without vaporizing, the effect can bemaintained for a long time. The preferable amount in this case isusually 0.00 wt % to 20 wt %, more preferably 0.01 wt % to 10 wt %. Ifthe amount is less than 0.001 wt %, the ultraviolet ray defense effectmay be inadequate. If the amount is greater than 20 wt %, it may bedifficult to form of the external skin preparation.

[0037] The present invention is explained in more fully by the followingexamples, but, the present invention is not restricted to theseexamples. The following are the manufacturing examples of pyridazinederivatives of the present invention.

[0038] 1 A method synthesizing a 4,5-Dimorphorino-3-hydroxypyridazine

[0039] 4,5-Dichloro-3-hydroxypyridazine (25.0 g, 0.151 mol=about 17 wt %in reaction solusion) was dissolved to morpholine (120 ml=100 vol %).The mixture was heated at 70° C. or more for 24 hours. After beingcooled, deposited crystal was filtered. White crystal of4,5-Dimorpholibo-3-hydroxypyridazine (37.2 g, yield percentage 92%) wasobtained.

[0040] Melting point 256 to 257° C. (Decomposition) (Capil.)

[0041] Next, chemical analysis values of the obtained compound wereshown. Table 1 shows the result of elemental analysis. Next, the resultsof ¹H—NMR, ¹³C—NMR and MS spectra were shown. These chemical datasupport the desired compound. TABLE 1 Elemental analysis value C (%) H(%) N (%) Calcd.(*) (%) 54.12 6.81 21.04 Found (%) 54.25 6.72 21.11

[0042]¹H—NMR(DMSO—d₆, TMS, ppm)

[0043] δ: 3.21 (dd, 4H, J=4.4&4.9Hz: —CH₂—N—CH₂—), 3.23 (dd, 4H,J=4.4&4.9Hz: —CH₂—N—CH₂—), 3.62 (dd, 4H, J=4.4&4.9Hz: —CH₂—O—CH₂—), 3.70(dd, 4H, J=4.4&4.9Hz: —CH₂—O—CH₂—), 7.67 (s, 1H: pyridazine ring H-6),12.38 (s, 1H: OH)

[0044]¹³C—NMR: (DMSO—d₆, TMS, ppm) δ: 47.8 (—CH₂—N—CH₂—), 48.5(—CH₂—N—CH₂—), 66.1 (—CH₂—O—CH₂—), 66.6(—CH₂—O—CH₂—), 131.1, 132.6,141.0(pyridazine ring C-4, C-5, C-6), 160.7 (pyridazine ring C-3) MSspectrum: MW=266(C₁₂H₁₈N₄O₃=266.30)

[0045] 2 A method synthesizing a 4,5-Dimorpholino-3-hydroxyPyridazine

[0046] 4,5-Dibromo-3-hydroxypyridazine (25.0 g, 0.098 mol=about 17 wt %in reaction solution) was dissolved to morpholine (120 ml=100 vol %).The mixture was heated at 70° C. or higher for 24 hours. After beingcooled, deposited crystal was filtered. White crystal of4,5-Dimorpholibo-3-hydroxypyridazine (23.7 g, yield percentage 90%) wasobtained.

[0047] Melting point 256 to 257° C. (Decomposition) (Capil.)

[0048] Next, chemical analysis values for the obtained compound areshown. Table 2 shows the result of elementary analysis. Next, theresults of ¹H—NMR, ¹³C—NMR and MS spectra were shown. These chemicaldata support the desired components. TABLE 2 Elemental analysis value C(%) H (%) N (%) Calcd.(*) (%) 54.12 6.81 21.04 Found (%) 54.22 6.8221.09

[0049]¹H—NMR(DMSO—d₆, TMS, ppm) δ: 3.21 (dd, 4H, J=4.4&4.9 Hz:—CH₂—N—CH₂—), 3.23 (dd, 4H, J=4.4&4.9Hz: —CH₂—N—CH₂—), 3.62 (dd, 4H,J=4.4&4.9 Hz: —CH₂—O—CH₂—), 3.70 (dd, 4H, J=4.4&4.9 Hz: —CH₂—O—CH₂—),7.67 (s, 1H: pyridazine ring H-6), 12.38(s, 1H:OH) ¹³C—NMR: (DMSO—d₆,TMS, ppm) δ: 47.8 (—CH₂—N—CH₂—), 48.5(—CH₂—N—CH₂—), 66.1 (—CH₂—O—CH₂—),66.6 (—CH₂—O—CH₂—), 131.1, 132.6, 141.0 (pyridazine ring C-4, C-5, C-6),160.7 (pyridazine ring C-3) MS spectrum: MW=266(C₁₂H₁₈N₄O₃=266.30)

[0050] Next, test result for ultraviolet rays absorbing ability of thepyridazine derivatives of the present invention are shown.

Test 1 Absorption

[0051] Ultraviolet rays absorption spectrum of4,5-Dimorpholino-3-hydroxypyridazine (Solvent: water, Concentration: 10ppm, Light path: 1 cm) was measured by the spectrophotometer(Manufactured by Nihonbunko Inc., Trade name: Ubest-55). The result wasshown in FIG. 1.

[0052]FIG. 1 shows that a pyridazine derivative of the present inventioncan absorb strongly with respect to the entire wavelength range ofultraviolet rays, 290 nm to 400 nm, which reach the surface of theearth. Also, it shows hardly any absorption in visible range forwavelengths longer than 400 nm. Accordingly, pyridazine derivatives ofthe present invention is excellent in visual transparency.

Test Example 2 Ultraviolet Rays Prevention Effect

[0053] (i) Test method

[0054] The prevention effect test was carried out on a beach during thesummer. Equal amounts of sample were applied to the right and left sidesof the backs of test subjects. After direct sunlight exposure, thedegree of sunburn was evaluated in accordance with the followingcriteria. Each group consisted of 20 subjects.

[0055] (Criterion)

[0056] Remarkable effect: None or almost no sunburn symptom was found.

[0057] Positive effect: Slight sunburn symptom was found.

[0058] Negative effect: Strong sunburn symptom was found.

[0059] (Evaluation)

[0060] A: Subject of remarkable effect or positive effect is 80% ormore.

[0061] B: Subject of remarkable effect or positive effect is 50% or moreand less than 80%.

[0062] C: Subject of remarkable effect or positive effect is 30% or moreand less than 50%.

[0063] D: Subject of remarkable effect or positive effect is less than30%

[0064] (ii) Preparation of sample

[0065] (A) Lotion (Alcohol phase) 95% Ethanol 25.0 (wt %)Polyoxyethylene(25) hydrogenated castor oil 2.0 Ultraviolet absorbent(See Table 3) 0 to 20 Antiseptics q.s. Perfume q.s. (Water phase)Glycerol 5.0 Sodium hexametaphosphate q.s. Ion-exchanged water Balance(Manufacturing method)

[0066] Each of water phase and alcohol phase was prepared. Then each wasmixed.

[0067] (B) Cream Stearyl alcohol 7.0 (wt %) Stearic acid 2.0Hydrogenated Lanolin 2.0 Squalane 5.0 2-Octyldodecyl alcohol 6.0Polyoxyethylene(25) cetyl ether 3.0 Glyceryl monostearate 2.0 Propyleneglycol 5.0 Ultraviolet absorbent (See Table 4) 0 to 20 Perfume q.s.Sodium hydrogensulfite 0.03 Ethyl paraben 0.3 Ion-exchanged waterBalance (Manufacturing method)

[0068] The propylene glycol was added to ion-exchanged water and wasdissolved, which was kept at 70° C. by heating (Water phase). The othercomponents were mixed and melted by heating and was kept at 70° C. (Oilphase). The oil phase was added to the water phase, and an emulsion wasformed.. After it was homogeneously emulsified with a homogenixer, itwas cooled at 30° C. with stirring well.

[0069] (iii) Result

[0070] The result with regard to lotion (a), cream (b) were shown inTable 3 and 4, respectively. TABLE 3 UV Ultraviolet absorbent Amount (wt%) prevent effect 4,5-dimorpholino-3-hydroxypyridazine 20  A 10  A 5 A 1A 0.01  A 0.001  B 0.0005 C No combination 0 D

[0071] TABLE 4 UV Ultraviolet absorbent Amount (wt %) prevent effect4,5-dimorpholino-3-hydroxypyridazine 20  A 10  A 5 A 1 A 0.1   A 0.001 B 0.0005 C No combination 0 D

[0072] Table 3 and Table 4 show that external skin preparation includinga pyridazine derivative of the present ultraviolet ray prevention effectas an ultraviolet absorbent. Also, it shows that the preferable amountof pyridazine derivative and/or salt thereof of the present invention is0.001 wt % to 20 wt %. Also, having an amount greater than 20 wt % makesit difficult to form an external skin preparation.

[0073] Accordingly, the pyridazine derivatives of the present inventionhave excellent absorbing ability with regard to wide range ofultraviolet rays. The inventors have studied with regard to the amountof the present invention in an ultraviolet absorbent in external skinpreparation. The inventors have studied it with regard to skinirritation, photostability and inorganic powder.

Test Example 3 Skin Irritation Test

[0074] Sample (10 wt % of ultraviolet absorbent) is the same as testexample 2.

[0075] (i ) Continuous use test

[0076] The continuous use test by the healthy subjects was carried outwith one group of twenty subjects. A proper amount of each sample wasapplied to the face twice a day for 4 weeks. The evaluation standard ofTable 5 was judged. TABLE 5 Degree of skin reaction Score No symptom(Negative) 0 Very slight symptom (false negative) 1 Slight symptom (weakpositive) 2 Middle symptom (middle positive) 3 Strong symptom (strongpositive) 4

[0077] (Evaluation)

[0078] The calculated average score was evaluated by the next standard.

[0079] A: Average score is 0.

[0080] B: Average score is over 0 and less than 1.

[0081] C: Average score is 1 or more, and less than 2.

[0082] D: Average score is 2 or more.

[0083] The result was shown in Table 6. TABLE 6 Ultraviolet absorbentFormulation Judgment 4,5-dimorpholino-3-hydroxypyridazine Lotion A CreamA No combination Lotion A Cream A

[0084] (ii) Patch test

[0085] An occlusive patch test was carried out in the antebrachium partof healthy men and women subjects by finchamber for 24 hours. Each groupwas twenty subjects. The judgement standard is shown in Table 7. TABLE 7Degree of skin reaction Score No reaction (Negative) 0 Slight erythema(false positive) 1 Erythema (weak positive) 2 Erythema + edema (Middledegree positive) 3 Erythema + edema + papula (Strong positive) 4Erythema bullosum (Most strong positive) 5

[0086] (Evaluation)

[0087] Each of the calculated average scores was evaluated by thefollowing evaluation standard.

[0088] A: average score is 0.

[0089] B: average score is over 0 and less than 1.

[0090] C: average score is 1 or more and less than 2.

[0091] D: average score is 2 or more.

[0092] The result was shown in Table 8. TABLE 8 Ultraviolet absorbentFormulation Judgment 4,5-dimorpholino-3-hydroxypyridazine Lotion A CreamA No combination Lotion A Cream A

[0093] Table 6 and Table 8 shows that external preparation for skinincluding ultraviolet absorbent of the present invention does not causeskin irritation in continuous use test and patch test, Also, it isunderstood that external preparation for skin of the present is verysafe.

Test Example 4 Photostability Test

[0094] After an aqueous solution of the pyridazine derivative of thepresent invention was exposed to sunlight (Amount of solar radiationexposure 80 MJ/m²) for two weeks, residual yield and change ofappearance were checked. UV absorption spectrum (Solvent: water,concentration: 10 ppm, Light path: 1 cm) was measured byspectrophotometer. Area value was calculated by integrating over therange of 290 nm to 400 nm of the ultraviolet rays absorption spectrum.The area value was compared with the value before sunlight exposure.

[0095] (Evaluation standard)

[0096] The residual yield and change of area value of ultraviolet raysabsorption spectrum were evaluated by the following standard.

[0097] A: 95% or more of area value before sunlight exposure.

[0098] B: 90% or more and less than 95% of area value before sunlightexposure.

[0099] C: 70% or more and less than 90% of area value before sunlightexposure.

[0100] D: less than 70% of area value before sunlight exposure.

[0101] The result was shown in Table 9. TABLE 9 Change of area value ofUltraviolet absorbent Residual yield UV absorption spectrum4,5-dimorpholino-3- A A hydroxypyridazine

[0102] Table 9 shows that a pyridazine derivative of the presentinvention has a very high residual yield. Accordingly, pyridazinederivative of the present invention did not decomposed by directsunlight exposure for a long time. Also, the shape and area value ofultraviolet ray absorption spectrum did not change. Also, coloring anddeposition and so on in the appearance were not found.

Test Example 6 Stability Test In Case Of Including UV Shielding Agent OfInorganic Powder

[0103] The sun screen cream of the following formulation wasmanufactured. These were preserved for 2 months at 50° C. By visualobservation of discoloration, the inventors have checked stability whenusing an UV shielding agent of inorganic powder which is included asexternal skin preparation for the ultraviolet rays defense. Sun-screencream  (1) Ethyl cellulose 1.0 (wt %)  (2) Ethanol 5.0  (3) 2-Ethylhexylsuccinate 24.0  (4) Titanium dioxide 1.0  (5) Porous silicic anhydridepowder 1.0  (6) Spherical nylon powder 1.0  (7) Talc 1.0  (8) Sericite1.0  (9) Boron nitride 1.0 (10) Silicone treated mica 1.0 (11)Ultraviolet absorbent (See Table 10) 10.0 (12) Carboxymethylcellulose1.0 (13) Ion-exchanged water Balance (14) Antiseptics q.s. (15) Perfumeq.s.

[0104] (Manufacturing method)

[0105] After (2) was added to (1) and was swelled sufficiently, (3) to(11) was added thereto and was mixed with heating. The mixture wassufficiently dissolved with dispersing. This dispersed liquid was keptat 70° C. After this dispersed liquid was emulsified homogeneously byhomomixer with adding a mixture of (12) to (15) gradually, which wascooled to 30° C. with stirring well to obtain sun screen.

[0106] The result was shown in Table 10. TABLE 10 Ultraviolet absorbentDiscoloration 4,5-Dimorpholino-3-hydroxypyridazine No

[0107] Table 10 shows that discoloration is not found in a pyridazinederivative of the the present invention in the case where inorganicpowder is used.

[0108] Accordingly, pyridazine derivatives of the present invention donot cause skin irritation and excel in photostability. Also,discoloration does not result in case of use of inorganic powder.Accordingly, pyridazine derivatives of the present invention are veryuseful as an ultraviolet absorbent in an external skin preparation.

[0109] Next, the effect as a photostabilizer of pyridazine derivative ofthe present invention was studied.

[0110] First of all, the photostabilization effect and appearance changeof a composition in each pigment were studied by the followingevaluation formulation.

Formulation for Evaluation of Colorant Stabilization Effect

[0111] Material Amount (wt %) Ion-exchanged water to 100 Brucinedenatured alcohol 5 Glycerol 5 Dipropylene glycol 5 Polyoxyethylenehydrogenated castor oil 1 Methyl paraben 0.2 Lactic acid  0.006 Sodiumlactate 0.2 Photo-stabilizer (See Table 11 to 16) See Table 11 to 16Pigment (See Table 11 to 16) See Table 11 to 16 Total 100 

[0112] Each test sample was prepared. Observation of appearance change(visual evaluation) and measurement of color difference (ΔE) werecarried out in samples exposed to sunlight exposure (around 80 MJ).

[0113] Color difference was measured by Lab coordinate system withspectrophotometer. Color difference was calculated on the basis of thecolor before sunlight exposure. Namely, from measured value (L₁,a₁,b₁)before sunlight exposure, color difference (ΔE) was calculated byfollowing formula.

ΔE={(L₂−L₁)²+(a₂−a₁−a₁)²+(b₂−b₁)²}^(½)

[0114] Table 11 and Table 12 show the result of the combination of asingle colorant and various kinds of photostabilizer. TABLE 11 Sunlightexposure Test Colorant Photostabilizer (80 MJ) example Name Amount NameAmount ΔE Appearance  7 Red No. 227 0.0001 No 0 1.45 C  8 (D&C Red No.33) 4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.49 A  9 (Trade name:Fast Acid Magenta) 2-Hydroxy-4-methoxybenzophenone 0.05 0.71 B 102-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.80 B 11 Octylp-methoxycinnamate 0.05 1.22 C 124-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.95 B 13 Red No. 1060.0001 No 0 3.04 C 14 (Trade name: Acid Red 52)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.82 A 152-Hydroxy-4-methoxybenzophenone 0.05 1.01 B 162-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.98 B 17 Octylp-methoxycinnamate 0.05 1.95 C 184-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.02 B 19 Yellow No. 2030.001 No 0 2.77 C 20 (D&C Yellow No. 52)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.18 A 21 (Trade name:Quinoline Yellow WS) 2-Hydroxy-4-methoxybenzophenone 0.05 0.88 B 222-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.76 B 23 Octylp-methoxycinnamate 0.05 2.43 C 244-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.68 B 25 Yellow No. 50.001 No 0 1.83 C 26 (FD&C Yellow No. 6)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.43 A 27 (Trade name: SunsetYellow FCF) 2-Hydroxy-4-methoxybenzophenone 0.05 0.82 B 282-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.78 B 29 Octylp-methoxycinnamate 0.05 1.56 C 304-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.88 B

[0115] TABLE 12 Sunlight exposure Test Colorant Photostabilizer (80 MJ)example Name Amount Name Amount ΔE Appearance 31 Blue No. 1 0.0001 No 08.92 C 32 (FD&C Blue No. 1) 4,5-Dimorpholino-3-hydroxypyridazine 0.051.11 A 33 (Trade name: Brilliant Blue FCF)2-Hydroxy-4-methoxybenzophenone 0.05 1.76 B 342-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 1.67 B 35 Octylp-methoxycinnamate 0.05 5.23 C 364-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.49 B 37 Green No. 30.0001 No 0 2.12 C 38 (FD&C Green No. 3)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.31 A 39 (Trade name: FastGreen FCF) 2-Hydroxy-4-methoxybenzophenone 0.05 0.75 B 402-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 0.74 B 41 Octylp-methoxycinnamate 0.05 1.64 C 424-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.62 B 43 Red No. 2130.0001 No 0 3.79 C 44 (D&C Red No. 19)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.78 A 45 (Trade name:Rhodamine B) 2-Hydroxy-4-methoxybenzophenone 0.05 1.34 B 462-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 1.28 B 47 Octylp-methoxycinnamate 0.05 2.55 C 484-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.02 B 49 Red No. 4010.001 No 0 7.58 C 50 (Ext. D&C Red No. 3)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.71 A 51 (Trade name:Violamine R) 2-Hydroxy-4-methoxybenzophenone 0.05 1.18 B 522-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 1.39 B 53 Octylp-methoxycinnamate 0.05 4.76 C 544-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.02 B

[0116] Next, Table 13 shows the result of the combination of multiplepigments and various kinds of photostabilizer. TABLE 13 Sunlightexposure Test Colorant Photostabilizer (80 MJ) example Name Amount NameAmount ΔE Appearance 55 Red No. 227 0.0001 No 0 1.59 C 56 (Trade name:Fast Acid Magenta) 4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.59 A 57Yellow No. 5 0.0001 2-Hydroxy-4-methoxybenzophenone 0.05 0.88 B 58(Trade name: Sunset Yellow FCF)4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.80 B 59 Red No. 2270.0001 No 0 3.05 C 60 (Trade name: Fast Acid Magenta)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.78 A 61 Yellow No. 2030.0001 2-Hydroxy-4-methoxybenzophenone 0.05 1.05 B 62 (Trade name:Quinoline Yellow WS) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.12B 63 Red No. 106 0.00001 No 0 3.77 C 64 (Trade name: Acid Red 52)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.77 A 65 Yellow No. 2030.0001 2-Hydroxy-4-methoxybenzophenone 0.05 1.11 B 66 (Trade name:Quinoline Yellow WS) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.02B 67 Red No. 106 0.00001 No 0 4.45 C 68 (Trade name: Acid Red 52)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.55 A 69 Yellow No. 5 0.00012-Hydroxy-4-methoxybenzophenone 0.05 1.18 B 70 (Trade name: SunsetYellow FCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.92 B 71Yellow No. 203 0.0001 No 0 1.45 C 72 (Trade name: Quinoline Yellow WS)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.37 A 73 Yellow No. 5 0.00012-Hydroxy-4-methoxybenzophenone 0.05 0.52 A 74 (Trade name: SunsetYellow FCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.48 A 75 RedNo. 213 0.00001 No 0 3.89 C 76 (Trade name: Rhodamine B)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.97 A 77 Blue No. 1 0.000012-Hydroxy-4-methoxybenzophenone 0.05 1.26 B 78 (Trade name: BrilliantBlue FCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 1.17 B 79 RedNo. 401 0.0001 No 0 3.04 C 80 (Trade name: Violamine R)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.32 A 81 Blue No. 1 0.000012-Hydroxy-4-methoxybenzophenone 0.05 0.82 B 82 (Trade name: BrilliantBlue FCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.93 B 83 RedNo. 401 0.0001 No 0 4.54 C 84 (Trade name: Violamine R)4,5-Dimorpholino-3-hydroxypyridazine 0.05 0.73 A 85 Green No. 3 0.000012-Hydroxy-4-methoxybenzophenone 0.05 1.06 B 86 (Trade name: Fast GreenFCF) 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 0.99 B

[0117] Tables 11 to 13 show that the color difference ΔE in a pyridazinederivative (4,5-dimorpholino-3-hydroxypyridazine) of the presentinvention is very small in comparison with other photostabilizers. Also,the change of appearance of the composition is small. Accordingly, it isunderstood that pyridazine derivative of the present invention hasexcellent photo stability for colorant.

[0118] Next, the inventors studied the effective amount ofphotostabilizer of the present invention for pigment. Table 14 and Table15 show the result of combination of a pyridazine derivative of thepresent invention and a single colorant. TABLE 14 Sunlight Test ColorantPhotostabilizer exposure (80 MJ) example Name Amount Name Amount ΔEAppearance  87 Red No. 227 0.0001 4,5-Dimorpholino-3-hydroxypyridazine 01.45 C  88 (D&C Red No. 33) 0.02 0.71 A  89 (Trade name: Fast AcidMagenta) 0.05 0.49 A  90 0.1 0.22 A  91 0.00001 0 2.35 C  92 0.05 0.69 A 93 0.1 0.32 A  94 0.3 0.11 A  95 Red No. 106 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 3.04 C  96 (Trade name: Acid Red52) 0.03 0.95 A  97 0.05 0.82 A  98 0.1 0.43 A  99 0.00001 0 4.54 C 1000.05 1.01 A 101 0.1 0.55 A 102 0.3 0.12 A 103 Yellow No. 203 0.0014,5-Dimorpholino-3-hydroxypyridazine 0 2.77 C 104 (D&C Yellow No. 10)0.02 0.25 A 105 (Trade name: Quinoline Yellow WS) 0.05 0.18 A 106 0.10.08 A 107 0.0001 0 3.52 C 108 0.05 0.22 A 109 0.1 0.10 A 110 0.3 0.05 A111 Yellow No. 5 0.001 4,5-Dimorpholino-3-hydroxypyridazine 0 1.83 C 112(FD&C Yellow No. 6) 0.01 0.61 A 113 (Trade name: Sunset Yellow FCF) 0.050.43 A 114 0.1 0.22 A 115 0.0001 0 2.54 C 116 0.05 0.59 A 117 0.1 0.71 A118 0.3 0.22 A

[0119] TABLE 15 Sunlight Test Colorant Photostabilizer exposure (80 MJ)example Name Amount Name Amount ΔE Appearance 119 Blue No. 1 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 8.92 C 120 (FD&C Blue No. 1) 0.031.25 A 121 (Trade name: Brilliant Blue FCF) 0.05 1.11 A 122 0.1 0.70 A123 0.00001 0 8.02 C 124 0.05 1.00 A 125 0.1 0.62 A 126 0.3 0.25 A 127Green No. 3 0.0001 4,5-Dimorpholino-3-hydroxypyridazine 0 2.12 C 128(FD&C Green No. 3) 0.02 0.75 A 129 (Trade name: Fast Green FCF) 0.050.31 A 130 0.1 0.06 A 131 0.00001 0 3.02 C 132 0.03 0.56 A 133 0.1 0.08A 134 0.3 0.02 A 135 Red No. 213 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 3.79 C 136 (D&C Red No. 19) 0.031.11 B 137 (Trade name: Rhodamine B) 0.05 0.78 A 138 0.1 0.32 A 1390.00001 0 4.57 C 140 0.03 1.24 B 141 0.1 0.45 A 142 0.3 0.12 A 143 RedNo. 401 0.001 4,5-Dimorpholino-3-hydroxypyridazine 0 7.58 C 144 (Ext.D&C Red No. 3) 0.03 0.95 A 145 (Trade name: Violamine R) 0.05 0.71 A 1460.1 0.45 A 147 0.0001 0 8.28 C 148 0.05 0.82 A 149 0.1 0.56 A 150 0.30.19 A

[0120] Table 16 shows the result of combining a pyridazine derivative ofthe present invention and multiple colorant. TABLE 16 Sunlight TestColorant Photostabilizer exposure (80 MJ) example Name Amount NameAmount ΔE Appearance 151 Red No. 227 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 1.59 C 152 (Trade name: Fast AcidMagenta) 0.03 0.72 A 153 Yellow No. 5 0.0001 0.05 0.59 A 154 (Tradename: Sunset Yellow FCF) 0.1 0.18 A 155 Red No. 227 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 3.05 C 156 (Trade name: Fast AcidMagenta) 0.05 0.78 A 157 Yellow No. 203 0.0001 0.1 0.35 A 158 (Tradename: Quinoline Yellow WS) 0.3 0.14 A 159 Red No. 106 0.000014,5-Dimorpholino-3-hydroxypyridazine 0 3.77 C 160 (Trade name: Acid Red52) 0.05 0.77 A 161 Yellow No. 203 0.0001 0.1 0.25 A 162 (Trade name:Quinoline Yellow WS) 0.3 0.11 A 163 Red No. 106 0.000014,5-Dimorpholino-3-hydroxypyridazine 0 4.45 C 164 (Trade name: Acid Red52) 0.03 0.97 A 165 Yellow No. 5 0.0001 0.05 0.55 A 166 (Trade name:Sunset Yellow FCF) 0.3 0.12 A 167 Yellow No. 203 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 1.45 C 168 (Trade name: QuinolineYellow WS) 0.03 0.52 A 169 Yellow No. 5 0.0001 0.05 0.37 A 170 (Tradename: Sunset Yellow FCF) 0.1 0.12 A 171 Red No. 213 0.000014,5-Dimorpholino-3-hydroxypyridazine 0 3.89 C 172 (Trade name: RhodamineB) 0.03 1.21 A 173 Blue No. 1 0.00001 0.05 0.97 A 174 (Trade name:Brilliant Blue FCF) 0.1 0.73 A 175 Red No. 401 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 3.04 C 176 (Trade name: ViolamineR) 0.03 0.95 A 177 Blue No. 1 0.00001 0.05 0.32 A 178 (Trade name:Brilliant Blue FCF) 0.1 0.07 A 179 Red No. 401 0.00014,5-Dimorpholino-3-hydroxypyridazine 0 4.54 C 180 (Trade name: ViolamineR) 0.03 0.98 A 181 Green No. 3 0.00001 0.05 0.73 A 182 (Trade name: FastGreen FCF) 0.3 0.14 A

[0121] Tables 14 to 16 show that approximately 0.01 wt % toapproximately 0.3 wt % of pyridazine derivatives of the presentinvention is effective as a photostabilizer in approximately 0.00001 wt% to approximately 0.001 wt % of colorant. Also, although over 0.3 wt %of pyridazine derivative is possible, in case of external preparationfor skin, if the amount is greater than 20 wt % of pyridazinederivative, it is difficult to maintain the formulation of the externalskin preparation.

[0122] Next, the photostabilization effect for each perfume was studiedby the following evaluation formulation.

Formulation For Evaluation Of Perfume Stabilization Effect

[0123] Material Amount (wt %) Ion-exchanged water to 100 Brucinedenatured alcohol 5 Glycerol 5 Dipropylene glycol 5 Polyoxyethylenehydrogenated castor oil 1 Methyl paraben 0.2 Lactic acid  0.006 Sodiumlactate 0.2 Photo-stabilizer (See Table 17 to 22) See Table 17 to 22Perfume (See Table 17 to 22)  0.03 Total 100 

[0124] Each test sample was prepared. Change of smell of sample exposedto sunlight (80 MJ) was observed (judgement by perfumier).

[0125] Table 17 shows the result of combining of natural perfume andvarious photostabilizers. TABLE 17 Sunlight exposure Test Natural (80MJ) exam- perfume Photostabilizer Smell ple Name Name Amount evaluation183 Rose oil No 0 C 184 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine185 2-Hydroxy-4-methoxybenzo- 0.05 B phenone 1862-Hydroxy-4-methoxybenzo- 0.05 B phenone-5-sodium sulfonate 187 Octylp-methoxycinnamate 0.05 C 188 4-tert-Butyl-4′-methoxy- 0.05 Bdi-benzoylmethane 189 Jasmine No 0 C 190 oil 4,5-Dimorpholino-3-hydroxy-0.05 A pyridazine 191 2-Hydroxy-4-methoxybenzo- 0.05 B phenone 1922-Hydroxy-4-methoxybenzo- 0.05 B phenone-5-sodium sulfonate 193 Octylp-methoxycinnamate 0.05 C 194 4-tert-Butyl-4′-methoxy- 0.05 Bdi-benzoylmethane 195 Neroli oil No 0 C 196 4,5-Dimorpholino-3-hydroxy-0.1 A pyridazine 197 2-Hydroxy-4-methoxybenzo- 0.1 B phenone 1982-Hydroxy-4-methoxybenzo- 0.1 B phenone-5-sodium sulfonate 199 Octylp-methoxycinnamate 0.1 C 200 4-tert-Butyl-4′-methoxy- 0.1 Bdi-benzoylmethane 201 Lavender No 0 C 202 oil4,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 2032-Hydroxy-4-methoxybenzo- 0.1 B phenone 204 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 205 Octyl p-methoxycinnamate 0.1 C 2064-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 207 Ylang No 0 C 208ylang oil 4,5-Dimorpholino-3-hydroxy- 0.2 A pyridazine 2092-Hydroxy-4-methoxybenzo- 0.2 B phenone 210 2-Hydroxy-4-methoxybenzo-0.2 B phenone-5-sodium sulfonate 211 Octyl p-methoxycinnamate 0.2 C 2124-tert-Butyl-4′-methoxy- 0.2 B di-benzoylmethane

[0126] Table 17 shows that the change of smell in a pyridazinederivative (4,5-dimorpholino-3-hydroxypyridazine) of the presentinvention is very small in comparison with other photostabilizers.Accordingly, it is understood that pyridazine derivative of the presentinvention has an excellent photostabilization effect for naturalpurfume.

[0127] Table 18 shows the result of combining synthetic perfume andvarious photostabilizers. TABLE 18 Sunlight exposure Test Synthetic (80MJ) exam- perfume Photostabilizer Smell ple Name Name Amount evaluation212 Limonene No 0 C 213 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine214 2-Hydroxy-4-methoxybenzo- 0.05 B phenone 2152-Hydroxy-4-methoxybenzo- 0.05 B phenone-5-sodium sulfonate 216 Octylp-methoxycinnamate 0.05 C 217 4-tert-Butyl-4′-methoxy- 0.05 Bdi-benzoylmethane 218 Linalool No 0 C 219 4,5-Dimorpholino-3-hydroxy-0.05 A pyridazine 220 2-Hydroxy-4-methoxybenzo- 0.05 B phenone 2212-Hydroxy-4-methoxybenzo- 0.05 B phenone-5-sodium sulfonate 222 Octylp-methoxycinnamate 0.05 C 223 4-tert-Butyl-4′-methoxy- 0.05 Bdi-benzoylmethane 224 Citral No 0 C 225 4,5-Dimorpholino-3-hydroxy- 0.1A pyridazine 226 2-Hydroxy-4-methoxybenzo- 0.1 B phenone 2272-Hydroxy-4-methoxybenzo- 0.1 B phenone-5-sodium sulfonate 228 Octylp-methoxycinnamate 0.1 C 229 4-tert-Butyl-4′-methoxy- 0.1 Bdi-benzoylmethane 230 Linalyl No 0 C 231 acetate4,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 2322-Hydroxy-4-methoxybenzo- 0.1 B phenone 233 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 234 Octyl p-methoxycinnamate 0.1 C 2354-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 236 Rose No 0 C 237oxide 4,5-Dimorpholino-3-hydroxy- 0.2 A pyridazine 2382-Hydroxy-4-methoxybenzo- 0.2 B phenone 239 2-Hydroxy-4-methoxybenzo-0.2 B phenone-5-sodium sulfonate 240 Octyl p-methoxycinnamate 0.2 C 2414-tert-Butyl-4′-methoxy- 0.2 B di-benzoylmethane

[0128] Table 18 shows that the change of smell in a pyridazinederivative (4,5-dimorpholino-3-hydroxypyridazine) of the presentinvention is very small in comparison with other photostabilizers.Accordingly, it is understood that pyridazine derivatives of the presentinvention have an excellent photostabilization effect for syntheticpurfume.

[0129] Table 19 shows the result of combining base perfume and variousphotostabilizers. TABLE 19 Sunlight exposure Test Base (80 MJ) exam-perfume Photostabilizer Smell ple Name Name Amount evaluation 242 RoseNo 0 C 243 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine 2442-Hydroxy-4-methoxybenzo- 0.05 B phenone 245 2-Hydroxy-4-methoxybenzo-0.05 B phenone-5-sodium sulfonate 246 Octyl p-methoxycinnamate 0.05 C247 4-tert-Butyl-4′-methoxy- 0.05 B di-benzoylmethane 248 Muguet No 0 C249 4,5-Dimorpholino-3-hydroxy- 0.05 A pyridazine 2502-Hydroxy-4-methoxybenzo- 0.05 B phenone 251 2-Hydroxy-4-methoxybenzo-0.05 B phenone-5-sodium sulfonate 252 Octyl p-methoxycinnamate 0.05 C253 4-tert-Butyl-4′-methoxy- 0.05 B di-benzoylmethane 254 Woody No 0 C255 4,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 2562-Hydroxy-4-methoxybenzo- 0.1 B phenone 257 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 258 Octyl p-methoxycinnamate 0.1 C 2594-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 300 Fruity No 0 C 3014,5-Dimorpholino-3-hydroxy- 0.1 A pyridazine 3022-Hydroxy-4-methoxybenzo- 0.1 B phenone 303 2-Hydroxy-4-methoxybenzo-0.1 B phenone-5-sodium sulfonate 304 Octyl p-methoxycinnamate 0.1 C 3054-tert-Butyl-4′-methoxy- 0.1 B di-benzoylmethane 306 Spicy No 0 C 3074,5-Dimorpholino-3-hydroxy- 0.2 A pyridazine 3082-Hydroxy-4-methoxybenzo- 0.2 B phenone 309 2-Hydroxy-4-methoxybenzo-0.2 B phenone-5-sodium sulfonate 310 Octyl p-methoxycinnamate 0.2 C 3114-tert-Butyl-4′-methoxy- 0.2 B di-benzoylmethane

[0130] Table 19 shows that the change of smell in a pyridazinederivative (4,5-dimorpholino-3-hydroxypyridazine) of the presentinvention is very small in comparison with other photostabilizers.Accordingly, it is understood that pyridazine derivatives of the presentinvention have an excellent photo stabilization effect for base perfume.

[0131] Next, the inventors have studied the effective amount ofphotostabilizer for perfume. Table 20 shows the result of combining apyridazine derivative of the present invention and natural perfume.TABLE 20 Sunlight exposure Test Natural perfume Photostabilizer (80 MJ)example Name Name Amount evaluation 312 Tuberose oil 4,5-Dimorpholino-0.03 A 313 3-hydroxypyridazine 0 C 314 Clary sage oil 0.03 A 315 0 C 316Cloves oil 0.03 A 317 0 C 318 Peppermint oil 0.03 A 319 0 C 320 Geraniumoil 0.03 A 321 0 C 322 Patchouli oil 0.01 A 323 0 C 324 Sandals wood oil0.01 A 325 0 C 326 Cinnamon oil 0.01 A 327 0 C 328 Coriander oil 0.01 A329 0 C 330 Nutmeg oil 0.01 A 331 0 C 332 Pepper oil 0.001 A 333 0 C 334Lemon oil 0.001 A 335 0 C 336 Orange oil 0.1 A 337 0 C 338 Bergamot oil0.1 A 339 0 C 340 Opopanax oil 0.1 A 341 0 C 342 Vetiver oil 0.2 A 343 0C 344 Orris oil 0.2 A 345 0 C 346 Oakmoss oil 0.2 A 347 0 C 348 Moss oil0.2 A 349 0 C 350 Civet oil 0.2 A 351 0 C 352 Castoreum oil 0.3 A 353 0C 354 Ambergris oil 0.3 A 355 0 C

[0132] Table 20 shows that approximately 0.001 wt % to approximately 0.3wt % of a pyridazine derivative of the present invention is effective asa photostabilizer in approximately 0.03 wt % of natural perfume.

[0133] Next, Table 21 shows the result of combining a pyridazinederivative of the present invention and synthetic perfume. TABLE 21Sunlight exposure (80 MJ) Test Synthetic perfume Photostabilizer Smellexample Name Name Amount evaluation 356 β-Caryophyllene4,5-dimorpholino- 0.01 A 357 3-hydroxy- 0 C 358 cis-3-Hexenol pyridazine0.01 A 359 0 C 360 Farnesol 0.01 A 361 0 C 362 β-Phenylethyl 0.03 A 363alcohol 0 C 364 2,6-Nonadienal 0.03 A 365 0 C 366 α-Hexyl cinnamic 0.03A 367 aldehyde 0 C 368 β-Ionone 0.05 A 369 0 C 370 I-Carvone 0.05 A 3710 C 372 Cyclopentadecanone 0.05 A 373 0 C 374 Benzyl benzoate 0.1 A 3750 C 376 γ-Undecalactone 0.1 A 377 0 C 378 Eugenol 0.1 A 379 0 C 380Indole 0.2 A 381 0 C 382 Phenylacetaldehyde 0.2 A 383 dimethyl acetal 0C 386 Lyral 0.3 A 387 0 C 388 Lilial 0.3 A 389 0 C

[0134] Table 21 shows that approximately 0.01 wt % to approximately 0.3wt % of a pyridazine derivative of the present invention is effective asa photostabilizer for approximately 0.03 wt % of synthetic perfume.

[0135] Next, Table 22 shows the result of combining a pyridazinederivative of the present invention and a base perfume. TABLE 22 BaseSunlight exposure Test perfume Photostabilizer (80 MJ) example Name NameAmount Smell evaluation 390 Jasmine 4,5-Dimorpholino- 0.01 A 3913-hydroxypyridazine 0 C 392 Chypre 0.01 A 393 0 C 394 Citrus 0.03 A 3950 C 396 Green 0.05 A 397 0 C 398 Fougere 0.1 A 399 0 C 400 Oriental 0.1A 401 0 C 402 Aldehyde 0.2 A 403 0 C 404 Animal 0.3 A 405 0 C

[0136] Table 22 shows that approximately 0.01 wt % to approximately 0.3wt % of a pyridazine derivative of the present invention is effective asa photostabilizer for approximately 0.03 wt % of base perfume.

[0137] Next, the photo stabilization effect and changes in appearance indrug compositions were studied according to the following evaluationformulation.

Formulation For Evaluation Of Drug Stabilization Effect

[0138] Material Amount (wt %) Ion-exchanged water to 100 Brucinedenatured alcohol 5 Glycerol 5 Dipropylene glycol 5 Polyoxyethylenehydrogenated castor oil 1 Methyl paraben 0.2  Lactic acid 0.006 Sodiumlactate 0.2  Stabilizer (See Table 23) See Table 23 Drug (See Table 23)See Table 23 Total 100 

[0139] Each test sample was prepared. Appearance changes of the samplesexposed to sunlight (80 MJ) was observed (visual evaluation). Also,residual yield was measured by liquid chromatography.

[0140] Next, Table 23 shows the result of combining a pyridazinederivative of the present invention and a drug. TABLE 23 Sunlightexposure (80 MJ) Test Drug Photostabilizer Residual yield Example NameAmount Name Amount [%] Appearance 406 Salicylic acid 0.1 No 0 87.6 C 4074,5-Dimorpholino-3-hydroxypyridazine 0.05 100.3 A 4082-Hydroxy-4-methoxybenzophenone 0.05 98.2 B 4092-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 98.0 B 410 Octylp-methoxycinnamate 0.05 92.2 C 4114-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 97.2 B 412 Dipotassiumglycyrrhizinate 0.05 No 0 85.1 C 4134,5-Dimorpholino-3-hydroxypyridazine 0.05 100.3 A 4142-Hydroxy-4-methoxybenzophenone 0.05 97.8 B 4152-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 97.5 B 416 Octylp-methoxycinnamate 0.05 90.8 C 4174-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 96.6 B 418 L-ascorbicacid 2-(dl-α- 0.01 No 0 69.0 C 419 tocopheryl hydrogen4,5-Dimorpholino-3-hydroxypyridazine 0.05 99.4 A 420 phosphate)potassium salt 2-Hydroxy-4-methoxybenzophenone 0.05 95.4 B 4212-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 95.0 B 422 Octylp-methoxycinnamate 0.05 82.1 C 4234-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 94.5 B 4242-o-α-α-glucopyranosyl- 2.0 No 0 84.7 C 425 L-ascorbic acid4,5-Dimorpholino-3-hydroxypyridazine 0.05 99.3 A 4262-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 97.8 B 4272-Hydroxy-4-methoxybenzophenone 0.05 97.3 B 428 Octyl p-methoxycinnamate0.05 92.3 C 429 4-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 97.0 B430 Dibutylhydroxytoluene 0.01 No 0 48.0 C 4314,5-Dimorpholino-3-hydroxypyridazine 0.05 98.8 A 4322-Hydroxy-4-methoxybenzophenone 0.05 95.2 B 4332-Hydroxy-4-methoxybenzophenone-5-sodium sulfonate 0.05 94.8 B 434 Octylp-methoxycinnamate 0.05 71.7 C 4354-tert-Butyl-4′-methoxy-di-benzoylmethane 0.05 95.2 B

[0141] Table 23 shows that residual yield of a drug combined with apyridazine derivative (4,5-dimorpholino-3-hydroxypyridazine) of thepresent invention is very high in comparison with otherphotostabilizers. Also, appearance changes of the composition is small.Accordingly, it is understood that pyridazine derivatives of the presentinvention have an excellent photostabilization effect on drugs.

[0142] The inventors have attempted to improve the photostabilzationeffect by combining the composition with sequestering agent.

[0143] First of all, the photostabilization effect and appearancechanges of a composition for each pigment were studied by the followingevaluation formulation.

Formulation For Evaluation Of Pigment Stabilization Effect

[0144] (Sequestering agent combination) Material Amount (wt %)Ion-exchanged water to 100 Brucine denatured alcohol 5 Glycerol 5Dipropylene glycol 5 Polyoxyethylene hydrogenated castor oil 1 Methylparaben 0.2 Lactic acid  0.006 Sodium lacate 0.2 Sequestering agent (SeeTable 24 to 26) See Table 24 to 26 4,5-Dimorpholino-3-hydroxypyridazineSee Table 24 to 26 Pigment (see Table 24 to 26) See Table 24 to 26 Total100 

[0145] Each test sample was prepared. Observation of appearance changes(visual evaluation) and measurement of color difference (ΔE) werecarried out for samples exposed to sunlight (around 80 MJ).

[0146] Color difference was measured by Lab coordinate system withspectrophotometer. Color difference was calculated based on the colorbefore sunlight exposure. Namely, from the measured value (L₁,a₁,b₁)before sunlight exposure, color difference (ΔE) was calculated byfollowing formula.

ΔE={(L₂−L₁)²+(a₂−a₁)²+(b₂−b₁)² }^(½)

[0147] Table 24 and Table 25 shows the result of combining a singlepigment, a pyridazine derivative of the present invention and varioussequestering agents. TABLE 24 Photo- Sunlight Test Colorant SequesteringAgent stabilizer exposure (80 MJ) Example Name Amount Name Amount AmountΔE Appearance 436 Red No. 227 0.0001 — 0 0 1.45 C 437 (D&C Red No. 33)0.01 0.98 B 438 (Trade name: Fast Acid Magenta) Trisodiumethylenediamine 0.02 0 1.40 C 439 tetraacetate 0.01 0.62 A 440 Sodiummetaphosphate 0.02 0 1.37 C 441 0.01 0.84 B 442 Trisodium hydroxyethyl0.02 0 14.3 C 443 ethylenediamine triacetate 0.01 0.58 A 444 Red No. 1060.0001 — 0 0 3.04 C 445 (Trade name: Acid Red 52) 0.02 1.23 B 446Trisodium ethylenediamine 0.02 0 2.98 C 447 tetraacetate 0.02 0.84 A 448Sodium metaphosphate 0.02 0 2.88 C 449 0.02 0.77 A 450 Sodiumpolyphosphate 0.02 0 2.92 C 451 0.02 0.85 A 452 Yellow No. 203 0.001 — 00 2.77 C 453 (D&C Yellow No. 10 0.01 0.95 B 454 (Trade name: QuinolineYellow WS) Trisodium ethylenediamine 0.02 0 2.73 C 455 tetraacetate 0.010.28 A 456 Sodium metaphosphate 0.02 0 2.74 C 457 0.01 0.22 A 458Trisodium hydroxyethyl 0.02 0 2.68 C 459 ethylenediamine triacetate 0.010.25 A 460 Yellow No. 5 0.001 — 0 0 1.83 C 461 (FD&C Yellow No. 6) 0.010.61 B 462 (Trade name: Sunset Yellow FCF) Trisodium ethylenediamine0.02 0 1.75 C 463 tetraacetate 0.01 0.32 A 464 Sodium metaphosphate 0.020 1.77 C 465 0.01 0.36 A 466 Sodium polyphosphate 0.02 0 1.75 C 467 0.010.33 A

[0148] TABLE 25 Photo- Sunlight Test Colorant Sequestering Agentstabilizer exposure (80 MJ) Example Name Amount Name Amount Amount ΔEAppearance 468 Blue No. 1 0.0001 — 0 0 8.92 C 469 (FC&C Blue No. 1) 0.021.74 B 470 (Trade name: Brilliant Blue FCF) Trisodium ethylenediamine0.03 0 8.50 C 471 tetraacetate 0.02 1.18 A 472 Sodium metaphosphate 0.030 8.02 C 473 0.02 1.00 A 474 Trisodium hydroxyethyl 0.03 0 7.92 C 475ethylenediamine triacetate 0.02 1.08 A 476 Green No. 3 0.0001 — 0 0 2.12C 477 (FD&C Green No. 3) 0.02 0.75 B 478 (Trade name: Fast Green FCF)Trisodium ethylenediamine 0.03 0 2.08 C 479 tetraacetate 0.02 0.48 A 480Sodium metaphosphate 0.03 0 2.02 C 481 0.02 0.28 A 482 Sodiumpolyphosphate 0.03 0 2.1 C 483 0.02 0.52 A 484 Red No. 213 0.0001 — 0 03.79 C 485 (FD&C Red No. 19) 0.03 2.12 B 486 (Trade name: Rhodamine B)Trisodium ethylenediamine 0.05 0 3.66 C 487 tetraacetate 0.03 1.45 A 488Sodium metaphosphate 0.05 0 3.71 C 489 0.03 1.38 A 490 Trisodiumhydroxyethyl 0.05 0 3.72 C 491 ethylenediamine triacetate 0.03 1.41 A492 Red No. 401 0.001 — 0 0 7.58 C 493 (Ext. D&C Red No. 3) 0.03 0.95 A494 (Trade name: Violamine R) Trisodium ethylenediamine 0.1 0 7.22 C 495tetraacetate 0.03 0.71 A 496 Sodium metaphosphate 0.1 0 7.07 C 497 0.020.66 A 498 Sodium polyphosphate 0.1 0 7.14 C 499 0.02 0.78 A

[0149] Next, Table 26 is the results in compositions having variouspigments, a pyridazine derivative of the present invention and variouskinds of sequestering agents. TABLE 26 Photo- Sunlight Test ColorantSequestering Agent stabilizer exposure (80 MJ) Example Name Amount NameAmount Amount ΔE Appearance 500 Red No. 227 0.0001 — 0 0 1.59 C 501(Trade name: Fast Acid Magenta) 0.02 1.02 B 502 Yellow No. 5 0.0001Trisodium ethylenediamine 0.02 0 1.55 C 503 (Trade name: Sunset YellowFCF tetraacetate 0.02 0.71 A 504 Red No. 227 0.0001 — 0 0 3.05 C 505(Trade name: Fast Acid Magenta) 0.05 1.55 A 506 Yellow No. 203 0.0001Sodium metaphosphate 0.02 0 3.01 C 507 (Trade name: Quinoline Yellow WS)0.05 1.01 A 508 Red No. 106 0.00001 — 0 0 3.77 C 509 (Trade name: AcidRed 52) 0.02 1.10 A 510 Yellow No. 203 0.0001 Trisodium hydroxyethyl0.02 0 3.56 C 511 (Trade name: Quinoline Yellow WS) ethylenediaminetriacetate 0.02 0.75 A 512 Red No. 106 0.00001 — 0 0 4.45 C 513 (Tradename: Acid Red 52) 0.02 1.33 B 514 Yellow No. 5 0.0001 Trisodiumethylenediamine 0.02 0 4.26 C 515 (Trade name: Sunset Yellow FCF)tetraacetate 0.02 0.98 A 516 Yellow No. 203 0.0001 — 0 0 1.45 C 517(Trade name: Quinoline Yellow WS) 0.02 0.78 A 518 Yellow No. 5 0.0001Sodium metaphosphate 0.01 0 1.44 C 519 (Trade name: Sunset Yellow FCF)0.02 0.48 A 520 Red No. 213 0.00001 — 0 0 3.89 C 521 (Trade name:Rhodamine B) 0.02 1.88 B 522 Blue No. 1 0.00001 Trisodium hydroxyethyl0.03 0 3.85 C 523 (Trade name: Brilliant Blue FCF) ethylenediaminetriacetate 0.02 1.22 A 524 Red No. 401 0.0001 — 0 0 3.04 C 525 (Tradename: Violamine R) 0.02 1.36 A 526 Blue No. 1 0.00001 Trisodiumethylenediamine 0.03 0 3.02 C 527 (Trade name: Brilliant Blue FCF)tetraacetate 0.02 0.88 A 528 Red No. 401 0.0001 — 0 0 4.54 C 529 (Tradename: Violamine R) 0.02 1.45 B 530 Green No. 3 0.00001 Sodiummetaphosphate 0.03 0 4.23 C 531 (Trade name: Fast Green FCF) 0.02 0.73 A

[0150] Tables 24 to 26 show that color difference ΔE for compositionshaving pyridazine derivative (4,5-dimorpholino-3-hydroxypyridazine) ofthe present invention and a sequestering agent is very small incomparison with color difference ΔE for other compositions not having asequestering agent. Also, the change of appearance of the composition issmall. Accordingly, it is understood that pyridazine derivatives of thepresent invention have a better photostabilization effect for pigmentwhen combined with a sequestering agent.

[0151] Also, since a sequestering agent itself does not have aphotostabilization effect, combining a pyridazine derivative of thepresent invention and a sequestering agent has synergisticphotostabilization effect.

[0152] Next, for combinations with sequestering agent,photostabilization effect for each perfume was studied by the followingevaluation formulation.

Formulation For Evaluation Of Perfume Stabilization Effect

[0153] (Sequestering agent combination) Material Amount (wt %)Ion-exchanged water to 100 Brucine denatured alcohol 5 Glycerol 5Dipropylene glycol 5 Polyoxyethylene hydrogenated castor oil 1 Methylparaben 0.2 Lactic acid  0.006 Sodium lacate 0.2 Sequestering agent (SeeTable 27 to 29) See Table 27 to 29 4,5-Dimorpholino-3-hydroxypyridazineSee Table 27 to 29 Perfume (See Table 27 to 29)  0.03 Total 100

[0154] Each test sample was prepared. Smell change of samples exposed tosunlight (80 MJ) was observed (judgement by perfumier).

[0155] Table 27 shows the result of combining natural perfume, apyridazine derivative of the present invention and various sequesteringagents. TABLE 27 Sunlight exposure Test Natural Photo- (80 MJ) exam-perfume Sequestering agent stabilizer Smell ple Name Name Amount Amountevaluation 532 Rose oil    — 0 0 C 533 0.02 B 534 Trisodium 0.03 0 C 535ethylenediamine 0.02 A tetraacetate 536 Jasmine    — 0 0 C 537 oil 0.02B 538 Sodium 0.03 0 C 539 metaphosphate 0.02 A 540 Lavender    — 0 0 C541 oil 0.02 B 542 Trisodium 0.03 0 C 543 hydroxyethyl 0.02 Aethylenediamine triacetate 544 Pepper-    — 0 0 C 545 mint oil 0.01 B546 Trisodium 0.03 0 C 547 ethylenediamine 0.01 A triacetate 548 Orangeoil    — 0 0 C 549 0.05 B 550 Sodium 0.03 0 C 551 metaphosphate 0.05 A552 Ylang    — 0 0 C 553 ylang oil 0.02 B 554 Trisodium 0.03 0 C 555hydroxyethyl 0.02 A ethylenediamine triacetate 556 Bergamot    — 0 0 C557 oil 0.05 B 558 Trisodium 0.03 0 C 559 ethylenediamine 0.05 Atetraacetate 560 Musk oil    — 0 0 C 561 0.1 B 562 Sodium 0.03 0 C 563metaphosphate 0.1 A

[0156] Table 27 shows that smell change of a composition including apyridazine derivative (4,5-dimorpholino-3-hydroxypyridazine) of thepresent invention and a sequestering agent is very small in comparisonwith smell change of other compositions not having sequestering agent.Accordingly, it is understood that a pyridazine derivative of thepresent invention has a better photostabilization effect for naturalperfume by combining it with a sequestering agent.

[0157] Also, since the sequestering agent itself does not have aphotostabilization effect, combining a pyridazine derivative of thepresent invention and a sequestering agent has a synergisticphotostabilization effect.

[0158] Table 28 shows the result of combining a synthetic perfume, apyridazine derivative of the present invention and various sequesteringagents. TABLE 28 Test Synthetic perfume Sequestering agentPhotostabilizer Sunlight exposure (80 MJ) example Name Name AmountAmount Smell evaluation 564 Limonene — 0 0 C 565 0.02 B 566 Trisodiumhydroxyethyl 0.03 0 C 567 ethylenediamine triacetate 0.02 A 568cis-3-Hexenol — 0 0 C 569 0.02 B 570 Trisodium ethylenediamine 0.03 0 C571 tetraacetate 0.02 A 572 Citral — 0 0 C 573 0.01 B 574 Trisodiumhydroxyethyl 0.03 0 C 575 ethylenediamine triacetate 0.01 A 576 β-ionone— 0 0 C 577 0.01 B 578 Trisodium ethylenediamine 0.03 0 C 579tetraacetate 0.01 A 580 Oranthiol — 0 0 C 582 0.05 B 583 Sodiummetaphosphate 0.03 0 C 584 0.05 A 585 Benzyl benzoate — 0 0 C 585 0.02 B586 Trisodium hydroxyethyl 0.03 0 C 587 ethylenediamine triacetate 0.02A 588 Rose oxide — 0 0 C 589 0.05 B 590 Trisodium ethylenediamine 0.03 0C 591 tetraacetate 0.05 A 592 Lilial — 0 0 C 593 0.1 B 594 Sodiummetaphosphate 0.03 0 C 595 0.1 A

[0159] Table 28 shows that smell change of a composition including apyridazine derivative (4,5-dimorpholino-3-hydroxypyridazine) of thepresent invention and a sequestering agent is very small in comparisonwith smell change of other compositions not having a sequestering agent.Accordingly, it is understood that a pyridazine derivative of thepresent invention has a better photostabilization effect for syntheticperfume by combining it with a sequestering agent.

[0160] Also, since the sequestering agent itself does not have aphotostabilization effect, combining of a pyridazine derivative of thepresent invention and a sequestering agent has a synergisticphotostabilization effect.

[0161] Table 29 shows the result of combining a base perfume, apyridazine derivative of the present invention and various sequesteringagents. TABLE 29 Test Synthetic perfume Sequestering agentPhotostabilizer Sunlight exposure (80 MJ) example Name Name AmountAmount Smell evaluation 596 Rose — 0 0 C 597 0.02 B 598 Trisodiumhydroxyethyl 0.03 0 C 599 ethylenediamine triacetate 0.02 A 600 Jasmine— 0 0 C 601 0.02 B 602 Trisodium ethylenediamine 0.03 0 C 603tetraacetate 0.02 A 604 Muguet — 0 0 C 605 0.02 B 606 Sodiummetaphosphate 0.03 0 C 607 0.02 A 608 Green — 0 0 C 609 0.01 B 610Trisodium hydroxyethyl 0.03 0 C 611 ethylenediamine triacetate 0.01 A612 Oriental — 0 0 C 613 0.01 B 614 Trisodium ethylenediamine 0.03 0 C615 tetraacetate 0.01 A 616 Fruity — 0 0 C 617 0.03 B 618 Sodiummetaphosphate 0.03 0 C 619 0.03 A 620 Aldehyde — 0 0 C 621 0.05 B 622Trisodium hydroxyethyl 0.03 0 C 623 0.05 A 624 Animal — 0 0 C 625 0.1 B626 Trisodium ethylenediamine 0.03 0 C 627 tetraacetate 0.1 A

[0162] Table 29 shows that smell change of a composition including apyridazine derivative (4,5-dimorpholino-3-hydroxypyridazine) of thepresent invention and a sequestering agent is very small in comparisonwith smell change of other compositions not having a sequestering agent.Accordingly, it is understood that a pyridazine derivative of thepresent invention has a better photostabilization effect for baseperfume by combining it with a sequestering agent.

[0163] Also, since the sequestering agent itself does not have aphotostabilization effect, combining a pyridazine derivative of thepresent invention and a sequestering agent has a synergisticphotostabilization effect.

[0164] Next, when combined with a sequestering agent, thephotostabilization effect and appearance change of a composition foreach drug was studied by the following evaluation formulation.

Formulation For Evaluation Of Drug Stabilization Effect

[0165] (Sequestering agent combination) Material Amount (wt %)Ion-exchanged water to 100 Brucine denatured alcohol 5 Glycerol 5Dipropylene glycol 5 Polyoxyethylene hydrogenated castor oil 1 Methylparaben 0.2 Lactic acid  0.006 Sodium lactate 0.2 Sequestering agent(See Table 30) See Table 30 4,5-Dimorpholino-3-hydroxypyridazine SeeTable 30 Drug (See Table 30) See Table 30 Total 100 

[0166] Each test sample was prepared. Appearance change of the samplesexposed to sunlight (around 80 MJ) was observed (visual evaluation).Also, residual yield of a drug was measured by liquid chromatography.

[0167] Next, Table 30 shows the result of combining a drug, a pyridazinederivative of the present invention and various sequestering agents.TABLE 30 Sunlight exposure (80 MJ) Photo- Residual Test DrugSequestering Agent stabilizer yield Example Name Amount Name AmountAmount [%] Appearance 628 Salicylic acid 0.1 — 0 0 87.6 C 629 0.03 99.2B 630 Trisodium ethylenediamine 0.03 0 88.0 C 631 tetraacetate 0.03100.1 A 632 Dipotassium glycyrrhizinate 0.05 — 0 0 85.1 C 633 0.03 97.2A 634 Sodium metaphosphate 0.03 0 85.8 B 635 0.03 100.0 A 636 L-ascorbicacid 2-(dl-α-tocopheryl 0.01 — 0 0 69.0 C 637 hydrogen phosphate)potassium salt 0.03 98.5 B 638 Trisodium hydroxyethyl 0.03 0 70.1 C 639ethylenediamine triacetate 0.03 99.4 A 640 2-α-α-α-glucopyranosyl- 2.0 —0 0 84.7 B 641 L-ascorbic acid 0.03 98.3 A 642 Sodium metaphosphate 0.030 85.2 C 643 0.03 99.3 A 644 Dibutylhydroxytoluene 0.01 — 0 0 48.0 C 6450.03 95.8 B 646 Sodium metaphosphate 0.03 0 54.7 C 647 0.03 98.8 A

[0168] Table 30 shows that residual yield of a drug in a compositionhaving a pyridazine derivative (4,5-dimorpholino-3-hydroxypyridazine) ofthe present invention and a sequestering agent is very small incomparison with residual yield of a drug in other compositions nothaving a sequestering agent. Accordingly, it is understood thatpyridazine derivative of the present invention has a betterphotostabilization effect for a drug when combined with a sequesteringagent.

[0169] Also, since a sequestering agent itself does not have aphotostabilization effect, combining of pyridazine derivative of thepresent invention and a sequestering agent has a synergisticphotostabilization effect.

[0170] The following are examples of external skin preparations of thepresent invention. These examples do not limit the present invention.Amounts shown are weight percent. Example 1  Lotion (Alcohol phase)Ethanol 10.0  Oleyl alcohol 0.1 Polyoxyethylene(20) sorbitan monolaurate0.5 Polyoxyethylene(15) lauryl ether 0.54,5-Dimorpholino-3-hydroxypyridazine 5.0 Antiseptics q.s. Perfume q.s.(Water phase) 1,3-Butylene glycol 6.0 Glycerol 4.0 Ion-exchanged waterBalance (Manufacturing method)

[0171] Each of water phase and alcohol phase was prepared and furthermixed. Example 2  Lotion (Alcohol phase) Ethanol 10.0 Polyoxyethylene(20) oleyl ether 0.5 Antiseptics q.s. Perfume q.s. (Waterphase) Dipropylene glycol 6.0 Sorbitol 4.0 Polyethylene glycol 1500 5.04,5-Dimorpholino-3-hydroxypyridazine hydrogen chloride 20.0  Methylcellulose 0.2 Quince seed 0.1 Ion-exchanged water Balance (Manufacturingmethod)

[0172] A portion of the ion-exchanged water, methyl cellulose and quinceseed were mixed with stirring and a viscous liquid was prepared. Therest of the ion-exchanged water and other water phase ingredients weremixed with dissolving. The above-mentioned viscous liquid was added tothis and a homogeneous water phase was obtained. The prepared alcoholphase was added to the water phase and was mixed. Stearic acid 5.0Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glyceryl monostearate 3.0Propylene glycol 10.0 4,5-Dimorpholino-3-hydroxypyridazine 20.0Potassium hydroxide 0.2 Sodium hydrogensulfite 0.01 Antiseptics q.s.Perfume q.s. Ion-exchanged water Balance

[0173] Propylene glycol and potassium hydroxide were added toion-exchanged water and were dissolved. The mixture was heated and waskept at 70° C. (Water phase). A. mixture of the other components wasmelted with heating and was kept at 70° C. (Oil phase). The oil phasewas gradually added to the water phase and an emulsion was formed. Afterit was homogeneously emulsified with a homomixer, which was cooled to30° C. with sufficient stirring. Example 4  Cream Stearic acid 6.0Sorbitan monostearate 2.0 Polyoxyethylene(20) sorbitan monostearate 1.5Propylene glycol 10.0  4,5-Dimorpholino-3-hydroxypyridazine 1.0 Glyceryltrioctanoate 10.0  Squalene 5.0 Sodium hydrogensulfite  0.01 Ethylparaben 0.3 Perfume q.s. Ion-exchanged water Balance (Manufacturingmethod)

[0174] The propylene glycol and 4,5-dimorpholino-3-hydroxypyridazinewere added to ion-exchanged water and were dissolved. It was kept at 70°C. with heating (Water phase). A mixture of the other ingredients wasmelted with heating and was kept at 70° C. (Oil phase). The oil phasewas added gradually to the water phase and an emulsion was formed. Afterit was emulsified homogeneously with a homomixer, it was cooled to 30°C. with sufficient stirring. Example 5  Milky lotion Stearic acid 2.5Cetyl alcohol 1.5 Petrolatum 5.0 Liquid paraffin 10.0 Polyoxyethylene(10) monooleate 2.0 Polyethylene glycol 1500 3.0Triethanol amine 1.0 4,5-Dimorpholino-3-hydroxypyridazine hydrogenchloride 10.0  Sodium hydrogensulfite  0.01 Ethyl paraben 0.3Carboxyvinylpolymer  0.05 Perfume q.s. Ion-exchanged water Balance(Manufacturing method)

[0175] Carboxyvinylpolymer was dissolved in a small amount ofion-exchanged water (A phase). Polyethylene glycol 1500,4,5-dimorpholino-3-hydroxypyridazine hydrochloaide and triethanolaminewere added to the remainder of the ion-exchanged water, which wasdissolved with heating and was kept at 70° C. (Water phase). Mixture ofother ingredients was melted with heating and was kept at 70° C. (Oilphase). The oil phase was added to the water phase to form an emulsionwas formed. After A phase was added and was homogeneously emulsifiedwith a homomixer, it was cooled to 30° C. with sufficient stirring.Example 6  Gel 95% Ethanol 10.0  Dipropylene glycol 15.0 Polyoxyethylene(50) oleyl ether 2.0 Carboxyvinylpolymer 1.0 Sodiumhydroxide  0.15 4,5-Dimorpholino-3-hydroxypyridazine 2.0 Methyl paraben0.2 Perfume q.s. Ion-exchanged water Balance (Manufacturing method)

[0176] Carboxyvinylpolymer was dissolved in ion-exchanged waterhomogeneously (A phase). 4,5-Dimorpholino-3-hydroxypyridazine and POE(50) oleyl ether were dissolved in 95% ethanol, which was added to Aphase. After the ingredients other than sodium hydroxide were added,sodium hydroxide was added thereto, thereby neutralizing the compositionand increasing viscosity. Example 7  Essence (A phase) 95% Ethanol 10.0 Polyoxyethylene(20) octyldodecanol 1.0 Methyl paraben  0.15 Pantothenylethylether 0.1 (B phase) Potassium hydroxide 0.1 (C phase) Glycerol 5.0Dipropylene glycol 10.0  Sodium hydrogensulfite  0.03Carboxyvinylpolymer 0.2 4,5-Dimorpholino-3-hydroxypyridazine 0.1Ion-exchanged water Balance (Manufacturing method)

[0177] Each of (A phase) and (C phase) was homogeneously dissolved. (Cphase) and additive (A phase) were solubilized. Next, (B phase) wasadded and mixed. Example 8  Pack (A phase) Dipropylene glycol 5.0Polyoxyethylene(60) hydrogenated castor oil 5.0 (B phase) Olive oil 5.0Tocopheryl acetate 0.2 Ethyl paraben 0.2 Perfume 0.2 (C phase)4,5-Dimorpholino-3-hydroxypyridazine 3.0 Sodium hydrogensulfite 0.03Polyvinyl alcohol 13.0 (Saponification degree 90, Polymerization degree2000) Ethanol 7.0 Ion-exchanged water Balance (Manufacturing method)

[0178] Each of A phase, (B phase) and (C phase) was homogeneouslydissolved. (A phase) was added to (B phase) and was solubilized. Next,(C phase) was added and mixed.

[0179] The above-mentioned examples 1 to 7 had an excellent ultravioletrays prevention effect. Also, in examples 1 to 8, skin trouble was notobserved at all. Example 9  Milky lotion (Oil phase) Stearyl alcohol 1.5Squalene 2.0 Petrolatum 2.5 Hydrogenated liquid lanolin 1.5 Eveningprimrose oil 2.0 Isopropylmyristate 5.0 Glyceryl monooleate 2.0Polyoxyethylene(60) hydrogenated castor oil 2.0 Tocopheryl acetate 0.05Ethyl paraben 0.2 Butyl paraben 0.1 Perfume q.s. (Water phase)4,5-Dimorpholino-3-hydroxypyridazine 1.04,5-Dimorpholino-3-hydroxypyridazine hydrochloride 1.0 Sodiumhydrogensulfite 0.01 Glycerol 5.0 Sodium hyaluronate 0.01Carboxyvinylpolymer 0.2 Potassium hydroxide 0.2 Ion-exchanged waterBalance (Manufacturing method)

[0180] Each of oil phase and water phase was dissolved at 70° C. Oilphase was mixed with water phase and was emulsified with emulsifier.Next, the result was cooled to 30° C. with a heat exchanger.

[0181] The milky lotion of example 9 had an excellent ultraviolet raysprevention effect. Also the skin trouble was not observed. Example 10 Solid powdery foundation  (1) Talc 15.0  (2) Sericite 10.0  (3)Spherical nylon powder 10.0  (4) Porous silicic anhydride powder 15.0 (5) Boron nitride 5.0  (6) Titanium dioxide 5.0  (7) Iron oxide 3.0 (8) Zinc stearate 5.0  (9) 4,5-Dimorpholino-3-hydroxypyridazine 5.0(10) Liquid petrolatum Balance (11) Glyceryl triisooctanoate 15.0 (12)Sorbitan sesquioleate 1.5 (13) Antiseptics q.s. (14) Perfume q.s.(Manufacturing method)

[0182] Each of (1) to (8) was mixed with crushing. A mixture ofcomponents of (9) to (14) were added thereto and was mixed withagitation. Solid foundation was obtained by forming to the container.Example 11  W/O emulsion foundation  (1) Spherical nylon 10.0  (2)Porous silicic anhydride powder 8.0  (3) Titanated mica 2.0  (4)Silicone treated sericite 2.0  (5) Silicone treated mica 12.0  (6)Silicone treated titanium dioxide 5.0  (7) Silicone treated iron oxide2.0  (8) Ion-exchanged water Balance  (9)4,5-Dimorpholino-3-hydroxypyridazine 3.0 (10)Decamethylcyclopentasiloxane 18.0 (11) Dimethylpolysiloxane 5.0 (12)Squalane 1.0 (13) Polyoxyethylene denatured dimethylpolysiloxane 2.0(14) Antiseptics q.s. (15) Perfume q.s. (Manufacturing method)

[0183] Ingredients (9) to (15) were mixed and were homogeneouslydissolved. A crushed (1) to (7) were added thereto and dispersed. (8)was added to this dispersion liquid and was emulsified. A W/O emulsionfoundation was obtained by forming to container. Example 12  Face powder (1) Talc Balance  (2) Sericite 10.0  (3) Spherical nylon powder 10.0 (4) Boron nitride 5.0  (5) Iron oxide 3.0  (6) Magnesium carbonate 5.0 (7) Squalane 3.0  (8) Glyceryl triisooctanoate 2.0  (9) Sorbitansesquioleate 2.0 (10) 4,5-Dimorpholino-3-hydroxypyridazine 0.1 (11)Antiseptics q.s. (12) Perfume q.s. (Manufacturing method)

[0184] Each ingredient of (1) to (6) was mixed and crushed. Mixture ofeach ingredient of (7) to (12) was added and mixed with agitation and aface powder was obtained. Example 13  Eye shadow  (1) Talc Balance  (2)Mica 15.0  (3) Spherical nylon powder 10.0  (4) Boron nitride 5.0  (5)Iron oxide 3.0  (6) Titanium oxide coated mica 5.0  (7) Squalane 3.0 (8) Glyceryl triiso octanoate 2.0  (9) Sorbitan sesquioleate 2.0 (10)4,5-Dimorpholino-3-hydroxypyridazine 2.0 (11) Antiseptics q.s. (12)Perfume q.s. (Manufacturing method)

[0185] Components of (1) to (6) were crushed and mixed. Furthermore, amixture of the components of (7) to (12) was added thereto, which wasmixed with agitation and an eye shadow was obtained. Example 14 Lipstick  (1) Carnauba wax 0.5  (2) Candelilla wax 5.0  (3) Ceresin10.0  (4) Squalane Balance  (5) Glyceryl triisostearate 10.0  (6)Glyceryl diisostearate 20.0  (7) 4,5-Dimorpholino-3-hydroxypyridazine1.0  (8) Macademia nut fatty acid cholesteryl 4.0  (9) Synthetic sodiummagnesium silicate 0.5 (10) Hydrophobic silica 0.5 (11) Ion-exchangedwater 2.0 (12) Colorant q.s. (13) Antiseptics q.s. (14) Perfume q.s.(Manufacturing method)

[0186] Ingredient (9) and (10) were dispersed to (8) melted at 60° C.(11) was added to this and was stirred sufficiently. This was added toheated and dissolved (1) to (7) and was agitated sufficiently. After(12) to (14) was added thereto which was dispersed with stirring,lipstick was obtained by molding.

[0187] Makeup cosmetics of examples 10 to 14 have an excellentultraviolet ray prevention effect. No skin trouble or no discolorationwas observed. Example 15  Hair form (Formulation for undiluted solution)(1) Acrylic resin/alkanolamine solution (50%) 8.0 (2) Polyoxyethylenehydrogenated castor oil q.s. (3) Liquid petrolatum 5.0 (4) Glycerol 3.0(5) Perfume q.s. (6) Antiseptics q.s. (7) Ethanol 15.0 (8)4,5-Dimorpholino-3-hydroxypyridazine 0.01 (9) Ion-exchanged waterBalance (Formulation for filling) (1) Undiluted solution 90.0 (2)Liquefied petroleum gas 10.0 (Manufacturing method)

[0188] Liquid petrolatum was added to dissolved glycerol andpolyoxyethylene hydrogenated castor oil and was homogeneously emulsifiedwith a homomixer. This was added to solution of the other ingredients.After the undiluted solution was filled a can, the valve was fixed andgas was added. (1) Polyoxypropylene(40) butyl ether 20.0 (2)Polyoxyethylene hydrogenated castor oil  1.0 (3) Ethanol 50.0 (4)Perfume q.s. (5) Antiseptics q.s. (6) Colorant q.s. (7)4,5-Dimorpholino-3-hydroxypyridazine  2.0 (8) Ion-exchanged waterBalance

[0189] Polyoxypropylene (40) butyl ether, polyoxyethylene hydrogenatedcastor oil, 4,5-dimorpholino-3-hydroxypyridadine, perfume andantiseptics were dissolved in ethanol. Colorant was dissolved inion-exchanged water. Water phase was added to Ethanol phase and wasfiltered with filter paper. Example 17  Hair spray (Formulation ofundiluted solution) (1) Acrylic resin/alkanolamine solution (50%) 7.0(2) Cetyl alcohol 0.1 (3) Silicone oil 0.3 (4) Ethanol Balance (5)Perfume q.s. (6) 4,5-Dimorpholino-3-hydroxypyridazine 2.0 (7)Ion-exchanged water 3.0 (Formulation for filling) (1) Undiluted solution50.0 (2) Liquefied petroleum gas 50.0 (Manufacturing method)

[0190] Other ingredients were added to ethanol and dissolved and theresult was filtered. After undiluted solution was added to a can and thevalve was fixed, gas was added. Example 18  Hair tonic (1)4,5-Dimorpholino-3-hydroxypyridazine 3.0 (2) Hydrogenated castor oilethyleneoxide (40 mol) additives 2.0 (3) Ethanol 60.0  (4) Perfume q.s.(5) Ion-exchanged water Balance (Manufacturing method)

[0191] The hydrogenated castor oil, ethylene oxide (40 moles) additivesand 4,5-dimorpholino-3-hydroxypyridazine were dissolved in ethanol. Theethanol phase and water phase were mixed and perfume was added.

[0192] The cosmetics for hair and scalp of examples 15 to 18 had anexcellent ultraviolet ray prevention effect. Also, scalp trouble anddiscoloration over of time were not observed. Example 19  Lotion(Alcohol phase) Ethanol 10.0  Oleyl alcohol 0.1 Polyoxyethylene(20)sorbitan monolaurate 0.5 Polyoxyethylene(15) lauryl ether 0.5Dibutylhydroxy toluene  0.01 Antiseptics q.s. Perfume q.s. (Water phase)L-ascorbic acid 2-(dl-α-tocopheryl hydrogen phosphate)  0.02 potassiumsalt 4,5-Dimorpholino-3-hydroxypyridazine 1.0 1,3-Butylene glycol 6.0Glycerol 4.0 Ion-exchanged water Balance (Manufacturing method)

[0193] The water phase and alcohol phase that were prepared individuallywere mixed. Example 20  Cream Stearic acid 5.0 Stearyl alcohol 4.0Isopropyl myristate 18.0  Glyceryl monostearate 3.0 Propylene glycol10.0  4,5-Dimorpholino-3-hydroxypyridazine 0.1 L-ascorbic acid2-(dl-α-tocopheryl hydrogen phosphate)  0.01 potassium salt Potassiumhydroxide 0.2 Dibutylhydroxytoluene  0.01 Sodium hydrogensulfite  0.01Antiseptics q.s. Perfume q.s. Ion-exchanged water Balance (Manufacturingmethod)

[0194] Propylene glycol, L-ascorbic acid 2-(dl-α-tocopheryl hydrogenphosphate) potassium salt, 4,5-dimorpholino-3-hydroxypyridazine andpotassium hydroxide were added to ion-exchanged water and weredissolved. It was kept with heating at 70° C. (Water phase). Otheringredients were melted with heating and kept at 70° C. (Oil phase). Theoil phase was added gradually to the water phase and was emulsifiedpreliminarily. After oil phase was added to water phase and wasemulsified homogeneously with a homomixer, it was cooled to 30° C. withsufficient stirring. Example 21  Emulsion Stearic acid 2.5 Cetyl alcohol1.5 Petrolatum 5.0 Liquid petrolatum 10.0  Polyoxyethylene(10)monooleate 2.0 Polyethylene glycol 1500 3.0 Triethanolamine 1.0L-ascorbic acid 2-(dl-α-tocopheryl hydrogen phosphate)  0.01 potassiumsalt 4,5-Dimorpholino-3-hydroxypyridazine 0.1 Dibutylhydroxytoluene 0.01 Ethyl paraben 0.3 Carboxyvinylpolymer  0.05 Perfume q.s.Ion-exchanged water Balance (Manufacturing method)

[0195] Carboxyvinylpolymer was dissolved in a small amount ofion-exchanged water (A phase). Polyethylene glycol 1500, L-ascorbic acid2-(dl-α-tocopheryl hydrogen phosphate) potassium salt,4,5-dimorpholino-3-hydroxypyridazine and triethanolamine were added tothe remainder of the ion-exchanged water. It was dissolved with heatingand was kept at 70° C. (Water phase). A mixture of other ingredients wasmelted with heating and was kept at 70° C. (Oil phase). The oil phasewas added to the water phase and was emulsified preliminarily. After Aphase was added thereto and was emulsified homogeneously with ahomomixer, which was cooled to 30° C. with sufficient stirring. Example22  Enamel Nitrocellulose (½ Second) 10.0 Alkyd resin 10.0Acetyltributyl citrate 5.0 4,5-Dimorpholino-3-hydroxypyridazine 0.1Ethyl acetate 20.0 Butyl acetate 20.0 Ethyl alcohol 5.0 Toluene 30.0Pigment q.s. Precipitation inhibitor q.s. (Manufacturing method)

[0196] Pigment was added to a part of acetyltributyl citrate and a partof alkyd resin and was kneaded well (Pigment part) Other ingredientswere mixed and dissolved. The pigment part was added to this, stirredwell, and homogeneously dispersed. Example 23  Transparent liquidshampoo Sodium lauryl polyoxyethylene(3) sulfate 30.0  (30% Aqueoussolution) Sodium lauryl sulfate (30% Aqueous solution) 10.0  Coconutfatty acid diethanolamide 4.0 Glycerol 1.04,5-Dimorpholino-3-hydroxypyridazine 0.1 Antiseptics q.s. colorant q.s.Perfume q.s. Sequestering agents q.s. Purified water Balance(Manufacturing method)

[0197] Each component was added to a purified water at 70° C. Themixture was homogeneously dissolved and cooled. Example 24  RinseSilicone oil 3.0 Liquid petrolatum 1.0 Cetyl alcohol 1.5 Stearyl alcohol1.0 Stearyltrimethyl ammonium chloride 0.74,5-Dimorpholino-3-hydroxypyridazine 0.5 Glycerol 3.0 Antiseptics q.s.Colorant q.s. Perfume q.s. Purified water Balance (Manufacturing method)

[0198] Stearyltrimethyl ammonium chloride, glycerol and pigment wereadded to a purified water and was kept at 70° C. (Water phase). Mixedother ingredients were dissolved with heating and was kept at 70° C.(Oil phase). The oil phase was added to the water phase. The mixture wasemulsified with a homomixer, which was cooled with stirring.

[0199] Pyridazine derivatives and salts thereof of the presentinvention, as an ultraviolet absorbent absorbs strongly ultraviolet raysof all wavelengths with the range of 290 nm to 400 nm which reachsurface of the earth. Accordingly, this absorbent has excellentultraviolet ray absorption ability. Also, thereof it has high safety andhigh stability. Also, pyridazine derivatives and salts of the presentinvention demonstrate an excellent effect as a photostabilizer ofcolorant, perfume and drug. Especially, by combining a sequesteringagent, this effect can be synergistically enhanced. Accordingly, bycombining the pyridazine derivative of the present invention, theobtained external preparation for the skin has high ultraviolet raysprevention effect, good stability, good safety and good photostability.

[0200] Another use other than for the external skin preparations is anultraviolet ray absorption composition which has excellent ultravioletray prevention effect.

We claim:
 1. A pyridazine derivative having a formula (1):

or its salts thereof.
 2. A method for the manufacturing pyridazinederivative or its salts according to claim 1 comprising the process ofreacting at least 10 wt % of 4,5-dichloro-3-hydroxypyridazine or4,5-dibromo-3-hydroxypyridazine or a mixture thereof, with at least 20vol % of morpholine in a reaction solution at 70° C. or higher.
 3. Anultraviolet absorbent comprising the pyridazine derivative or its salts,according to claim 1 .
 4. An ultraviolet absorptive compositioncomprising the ultraviolet absorbent according to claim 3 .
 5. Aphotostabilizer comprising the pyridazine derivative or its saltsaccording to claim 1 .
 6. The photostabilizer according to claim 5 ,wherein said photostabilizer includes a sequestering agent.
 7. Anexternal preparation for skin comprising the ultraviolet absorbentaccording to claim 3 .
 8. The external skin preparation according toclaim 7 , wherein said external preparation for skin includes aninorganic powder.
 9. An external preparation for skin comprising thephotostabilizer according to claim 5 .
 10. An external preparation forskin comprising the photostabilizer according to claim 6 .
 11. Theexternal preparation for skin according to claim 7 , wherein saidexternal preparation for skin includes 0.001 wt % to 20 wt % of thepyridazine derivative or its salts thereof.
 12. The external preparationfor skin according to claim 8 , wherein said external preparation forskin includes 0.001 wt % to 20 wt % of the pyridazine derivative or itssalts thereof.
 13. The external preparation for skin according to claim9 , wherein said external preparation for skin includes 0.001 wt % to 20wt % of the pyridazine derivative or its salts thereof.
 14. The externalpreparation for skin according to claim 10 , wherein said externalpreparation for skin includes 0.001 wt % to 20 wt % of the pyridazinederivative or its salts thereof.